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The Creation of Cybrids Harboring Mitochondrial Haplogroups in the Taiwanese Population of Ethnic Chinese Background: An Extensive In Vitro Tool for the Study of Mitochondrial Genomic Variations  [PDF]
Tsu-Kung Lin,Hung-Yu Lin,Shang-Der Chen,Yao-Chung Chuang,Jiin-Haur Chuang,Pei-Wen Wang,Sheng-Teng Huang,Mao-Meng Tiao,Jin-Bor Chen,Chia-Wei Liou
Oxidative Medicine and Cellular Longevity , 2012, DOI: 10.1155/2012/824275
Abstract: Mitochondrial DNA (mtDNA) haplogroups may contribute to the development of aging-related diseases. A reliable in vitro cellular system for investigating the physiologic significance of mtDNA haplogroups is essential. This study aims to construct and characterize a series of cybrid cell lines harboring variant mtDNA haplogroups collected from healthy Taiwanese volunteers. Cybrid cells harboring different mtDNA haplogroups like B4a, B4b, B4c, B4d, B5, R, F1a, F2, D4e, D4a, D5b, D5a, E, M8, C, and N9a were prepared. Luminex 1000 and full-length mtDNA sequencing were used to confirm that mtDNA haplogroups of transmitochondrial cybrids were identical to their original donors. Cybrid B4b had a significantly lower oxygen consumption rate and higher mitochondrial membrane potential compared to F1a, B5, D5a, D4a, and N9a but had more susceptibility to H2O2-induced oxidative stress than cybrid F1a, D4a, and N9a. Cybrid N9a had better oxygen consumption and H2O2-challenged viability compared to B4b, F1a, B5, D5a, and D4a. A series of cybrid cells harboring the main haplogroups of the Taiwanese population with ethnic Chinese background has been developed in vitro. With this mtDNA haplogroup population, the underlying mechanisms of aging-related diseases may be better understood, and therapeutic interventions can be accelerated. 1. Introduction A double-membrane structure and a circular mitochondrial genome with its own transcription, translation, and protein assembly systems support the endosymbiotic origin of the mitochondria [1]. While most mitochondrial proteins are encoded by nuclear DNA and imported into the organelle, 13 are encoded by mitochondrial DNA. Human mitochondrial DNA (mtDNA) is a 16,568?bp circular double-stranded DNA molecule coding for 13 polypeptide components of the mitochondrial oxidative phosphorylation (OXPHOS) machinery, 2 ribosomal RNA molecules, and a set of 22 transfer RNA molecules [1–4]. More than 99% of mitochondrial proteins are encoded by the nuclear genome, translated on cytoplasmic ribosomes, and selectively imported into the appropriate mitochondrial compartment [5]. Mitochondrial DNA is inherited maternally, and each mitochondrion contains 2–10 mtDNA molecules [6]. Mitochondrial DNA has a very high mutation rate and when a mutation occurs, normal and mutant mitochondrial DNA can coexist within the same cell, known as heteroplasmy [5, 7]. Mitochondrial DNA defects are linked with a wide range of diseases known as mitochondrial encephalomyopathies. Over the last two decades, more than 100 pathologic defects of mtDNA have been
Associations of Mitochondrial Haplogroups B4 and E with Biliary Atresia and Differential Susceptibility to Hydrophobic Bile Acid  [PDF]
Mao-Meng Tiao,Chia-Wei Liou,Li-Tung Huang,Pei-Wen Wang,Tsu-Kung Lin,Jin-Bor Chen,Yao-Min Chou,Ying-Hsien Huang,Hung-Yu Lin,Chao-Long Chen,Jiin-Haur Chuang
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003696
Abstract: Mitochondrial dysfunction has been implicated in the pathogenesis of biliary atresia (BA). This study aimed to determine whether a specific mitochondrial DNA haplogroup is implicated in the pathogenesis and prognosis of BA. We determined 40 mitochondrial single nucleotide polymorphisms in 15 major mitochondrial haplogroups by the use of 24-plex PCR and fluorescent beads combined with sequence-specific oligonucleotide probes in 71 patients with BA and in 200 controls in the Taiwanese population of ethnic Chinese background. The haplogroup B4 and E prevalence were significantly lower and higher respectively, in the patients with BA than in the controls (odds ratios, 0.82 [p = 0.007] and 7.36 [p = 0.032] respectively) in multivariate logistic-regression analysis. The 3-year survival rate with native liver was significantly lower in haplogroup E than the other haplogroups (P = 0.037). A cytoplasmic hybrid (cybrid) was obtained from human 143B osteosarcoma cells devoid of mtDNA (ρ0 cell) and was fused with specific mtDNA bearing E and B4 haplogroups donated by healthy Taiwanese subjects. Chenodeoxycholic acid treatment resulted in significantly lower free radical production, higher mitochondrial membrane potential, more viable cells, and fewer apoptotic cybrid B4 cells than parental 143B and cybrid E cells. Bile acid treatment resulted in a significantly greater protective mitochondrial reaction with significantly higher mitochondrial DNA copy number and mitofusin 1 and 2 concentrations in cybrid B4 and parental cells than in cybrid E cells. The results of the study suggested that the specific mitochondrial DNA haplogroups B4 and E were not only associated with lower and higher prevalence of BA respectively, in the study population, but also with differential susceptibility to hydrophobic bile acid in the cybrid harboring different haplogroups.
Human Retinal Transmitochondrial Cybrids with J or H mtDNA Haplogroups Respond Differently to Ultraviolet Radiation: Implications for Retinal Diseases  [PDF]
Deepika Malik, Tiffany Hsu, Payam Falatoonzadeh, Javier Cáceres-del-Carpio, Mohamed Tarek, Marilyn Chwa, Shari R. Atilano, Claudio Ramirez, Anthony B. Nesburn, David S. Boyer, Baruch D. Kuppermann, S. Michal Jazwinski, Michael V. Miceli, Douglas C. Wallace, Nitin Udar, M. Cristina Kenney
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099003
Abstract: Background It has been recognized that cells do not respond equally to ultraviolet (UV) radiation but it is not clear whether this is due to genetic, biochemical or structural differences of the cells. We have a novel cybrid (cytoplasmic hybrids) model that allows us to analyze the contribution of mitochondrial DNA (mtDNA) to cellular response after exposure to sub-lethal dose of UV. mtDNA can be classified into haplogroups as defined by accumulations of specific single nucleotide polymorphisms (SNPs). Recent studies have shown that J haplogroup is high risk for age-related macular degeneration while the H haplogroup is protective. This study investigates gene expression responses in J cybrids versus H cybrids after exposure to sub-lethal doses of UV-radiation. Methodology/Principal Findings Cybrids were created by fusing platelets isolated from subjects with either H (n = 3) or J (n = 3) haplogroups with mitochondria-free (Rho0) ARPE-19 cells. The H and J cybrids were cultured for 24 hours, treated with 10 mJ of UV-radiation and cultured for an additional 120 hours. Untreated and treated cybrids were analyzed for growth rates and gene expression profiles. The UV-treated and untreated J cybrids had higher growth rates compared to H cybrids. Before treatment, J cybrids showed lower expression levels for CFH, CD55, IL-33, TGF-A, EFEMP-1, RARA, BCL2L13 and BBC3. At 120 hours after UV-treatment, the J cybrids had decreased CFH, RARA and BBC3 levels but increased CD55, IL-33 and EFEMP-1 compared to UV-treated H cybrids. Conclusion/Significance In cells with identical nuclei, the cellular response to sub-lethal UV-radiation is mediated in part by the mtDNA haplogroup. This supports the hypothesis that differences in growth rates and expression levels of complement, inflammation and apoptosis genes may result from population-specific, hereditary SNP variations in mtDNA. Therefore, when analyzing UV-induced damage in tissues, the mtDNA haplogroup background may be important to consider.
Survival and mitochondrial function in septic patients according to mitochondrial DNA haplogroup
Leonardo Lorente, Ruth Iceta, María M Martín, Esther López-Gallardo, Jordi Solé-Violán, José Blanquer, Lorenzo Labarta, César Díaz, Alejandro Jiménez, Julio Montoya, Eduardo Ruiz-Pesini
Critical Care , 2012, DOI: 10.1186/cc11150
Abstract: A prospective, multicenter, observational study was carried out in six Spanish ICUs. We included 96 patients with severe sepsis. We determined the mtDNA haplogroup, the COX specific activity/citrate synthase specific activity (COXa/CSa) ratio and the COX quantity/citrate synthase specific activity (COXq/CSa) ratio in circulating platelets at the time of diagnosis, day 4 and day 8. We used survival at 1 and 6 months as endpoints.Patients with the JT mtDNA haplogroup (n = 15) showed higher COXq/CSa ratio at day 4 (P = 0.04) and day 8 (P = 0.02) than those with other haplogroups (n = 81). Logistic regression analysis showed that the JT mtDNA haplogroup (odds ratio = 0.18; 95% confidence interval = 0.04 to 0.94; P = 0.04) and COXq/CSa ratio (odds ratio = 0.53; 95% confidence interval = 0.30 to 0.93; P = 0.03) were associated with 1-month survival after controlling for age and lactic acid levels.The novel findings of our study are that 1-month surviving septic patients showed higher COXq/CSa ratio than nonsurviving individuals, that patients from the JT mtDNA haplogroup showed a higher COXq/CSa ratio and that JT patients had a higher 1-month survival than patients from other mtDNA haplogroups.Sepsis is a common, expensive, and frequently fatal condition [1,2]. The physiopathologic mechanisms of sepsis are not well known, but it has been proposed that organ dysfunction during sepsis is associated with tissue hypoxia due to cellular inability to use oxygen because of mitochondrial dysfunction [3]. Respiratory complex IV or cytochrome c oxidase (COX) is responsible for most cellular oxygen consumption. We have recently found that platelet COX activities and quantities in 6-month-survival patients are significantly higher than those of patients who do not survive 6 months [4]. COX contains 13 polypeptides and three of them are encoded by mitochondrial DNA (mtDNA) [5]. We have also found that transmitochondrial cell lines (cybrids) harboring different mtDNA genetic background
Japanese Alzheimer’s Disease and Other Complex Disorders Diagnosis Based on Mitochondrial SNP Haplogroups  [PDF]
Shigeru Takasaki
International Journal of Alzheimer's Disease , 2012, DOI: 10.1155/2012/245038
Abstract: This paper first explains how the relations between Japanese Alzheimer’s disease (AD) patients and their mitochondrial SNP frequencies at individual mtDNA positions examined using the radial basis function (RBF) network and a method based on RBF network predictions and that Japanese AD patients are associated with the haplogroups G2a and N9b1. It then describes a method for the initial diagnosis of Alzheimer’s disease that is based on the mtSNP haplogroups of the AD patients. The method examines the relations between someone’s mtDNA mutations and the mtSNPs of AD patients. As the mtSNP haplogroups thus obtained indicate which nucleotides of mtDNA loci are changed in the Alzheimer’s patients, a person’s probability of becoming an AD patient can be predicted by comparing those mtDNA mutations with that person’s mtDNA mutations. The proposed method can also be used to diagnose diseases such as Parkinson’s disease and type 2 diabetes and to identify people likely to become centenarians. 1. Introduction Mitochondria are essential cytoplasmic organelles generating cellular energy in the form of adenosine triphosphate by oxidative phosphorylation. Because most cells contain hundreds of mitochondria, each having multiple copies of their mitochondrial DNA (mtDNA), each cell contains several thousand mtDNA copies. The mutation rate for mtDNA is very high, and when mtDNA mutations occur, the cells contain a mixture of wild-type and mutant mtDNAs. As the mutations accumulate, the percentage of mutant mtDNAs increases and the amount of energy produced within the cell can decline until it falls below the level necessary for the cell to function normally. When this bioenergetic threshold is crossed, disease symptoms appear and become progressively worse. Mitochondrial diseases encompass an extraordinary assemblage of clinical problems, usually involving tissues that require large amounts of energy, such as those in the heart, skeletal muscle, kidney, and endocrine glands [1–3]. Although there are reports that mtDNA mutations are related to aging and a wide variety of diseases—such as Alzheimer’s disease (AD), Parkinson’s disease (PD), type 2 diabetes (T2D) disease, and various kinds of cancer [4–20]—those reports focus on the amino acid replacements caused by mtDNA mutations. Mitochondrial functions can of course be affected directly by amino acid replacements, but they can also be affected indirectly by mutations in mtDNA control regions. It is, therefore, important to examine the relations between all mtDNA mutations and disease patients or centenarians. In the work
Mitochondrial Haplogroups H and J: Risk and Protective Factors for Ischemic Cardiomyopathy  [PDF]
Mariana Fernández-Caggiano, Javier Barallobre-Barreiro, Ignacio Rego-Pérez, María G. Crespo-Leiro, María Jesus Paniagua, Zulaika Grillé, Francisco J. Blanco, Nieves Doménech
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044128
Abstract: Background Since mitochondria are the principal source of reactive oxygen species (ROS), these organelles may play an important role in ischemic cardiomyopathy (IC) development. The mitochondrial genome may influence this disease. The aim of the present study was to test the relationship between IC development and the impact of single nucleotide polymorphisms (SNPs) in mitochondrial DNA (mtDNA) defining the mitochondrial haplogroups in a population study. Methodology and principal findings Ten major European haplogroups were identified by using the single base extension technique and by polymerase chain reaction-restriction fragment length polymorphism. Frequencies and Odds Ratios for the association between IC patients (n = 358) and healthy controls (n = 423) were calculated. No convincing associations between classical risk factors for ischemic cardiomyopathy development and haplogroups were found. However, compared to healthy controls, the prevalence of haplogroup H was significantly higher in IC patients (40.0% vs 50.0%, p-value = 0.039) while the frequency of haplogroup J was significantly lower (11.1% vs 5.6%, p-value = 0.048). The analysis of the SNPs characterizing the European mtDNA haplogroups showed that the m.7028C allele (40.0% vs 50.0%, p-value = 0.005) and m.14766C allele (43.0% vs 54.2%, p-value = 0.002) were overrepresented in IC patients, meanwhile the m.10398G allele (19.8% vs 13.1%, p-value = 0.015) and m.4216C allele (22.2% vs 16.5%, p-value = 0.044) were found as protective factors against IC. Conclusions and significance Our results showed that the haplogroups H and J were found as a risk and protective factors for ischemic cardiomyopathy development, respectively.
May “Mitochondrial Eve” and Mitochondrial Haplogroups Play a Role in Neurodegeneration and Alzheimer's Disease?
Elena Caldarazzo Ienco,Costanza Simoncini,Daniele Orsucci,Loredana Petrucci,Massimiliano Filosto,Michelangelo Mancuso,Gabriele Siciliano
International Journal of Alzheimer's Disease , 2011, DOI: 10.4061/2011/709061
Abstract: Mitochondria, the powerhouse of the cell, play a critical role in several metabolic processes and apoptotic pathways. Multiple evidences suggest that mitochondria may be crucial in ageing-related neurodegenerative diseases. Moreover, mitochondrial haplogroups have been linked to multiple area of medicine, from normal ageing to diseases, including neurodegeneration. Polymorphisms within the mitochondrial genome might lead to impaired energy generation and to increased amount of reactive oxygen species, having either susceptibility or protective role in several diseases. Here, we highlight the role of the mitochondrial haplogroups in the pathogenetic cascade leading to diseases, with special attention to Alzheimer's disease.
Mitochondrial Haplogroups Modify the Risk of Developing Hypertrophic Cardiomyopathy in a Danish Population  [PDF]
Christian M. Hagen, Frederik H. Aidt, Paula L. Hedley, Morten K. Jensen, Ole Havndrup, J?rgen K. Kanters, Johanna C. Moolman-Smook, Severin O. Larsen, Henning Bundgaard, Michael Christiansen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0071904
Abstract: Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in genes coding for proteins involved in sarcomere function. The disease is associated with mitochondrial dysfunction. Evolutionarily developed variation in mitochondrial DNA (mtDNA), defining mtDNA haplogroups and haplogroup clusters, is associated with functional differences in mitochondrial function and susceptibility to various diseases, including ischemic cardiomyopathy. We hypothesized that mtDNA haplogroups, in particular H, J and K, might modify disease susceptibility to HCM. Mitochondrial DNA, isolated from blood, was sequenced and haplogroups identified in 91 probands with HCM. The association with HCM was ascertained using two Danish control populations. Haplogroup H was more prevalent in HCM patients, 60% versus 46% (p = 0.006) and 41% (p = 0.003), in the two control populations. Haplogroup J was less prevalent, 3% vs. 12.4% (p = 0.017) and 9.1%, (p = 0.06). Likewise, the UK haplogroup cluster was less prevalent in HCM, 11% vs. 22.1% (p = 0.02) and 22.8% (p = 0.04). These results indicate that haplogroup H constitutes a susceptibility factor and that haplogroup J and haplogroup cluster UK are protective factors in the development of HCM. Thus, constitutive differences in mitochondrial function may influence the occurrence and clinical presentation of HCM. This could explain some of the phenotypic variability in HCM. The fact that haplogroup H and J are also modifying factors in ischemic cardiomyopathy suggests that mtDNA haplotypes may be of significance in determining whether a physiological hypertrophy develops into myopathy. mtDNA haplotypes may have the potential of becoming significant biomarkers in cardiomyopathy.
Mitochondrial DNA Haplogroups and Susceptibility to Prostate Cancer in a Colombian Population  [PDF]
D. Cano,C. F. Gomez,N. Ospina,J. A. Cajigas,H. Groot,R. E. Andrade,M. M. Torres
ISRN Oncology , 2014, DOI: 10.1155/2014/530675
Abstract: Prostate cancer (PC) is one of the most common cancers and the second leading cause of mortality from cancer in Colombian men. Mitochondrial DNA (mtDNA) haplogroups have been associated with the risk of PC. Several studies have demonstrated dramatic differences regarding the risk of PC among men from different ethnic backgrounds. The present study was aimed at assessing the relationship between mtDNA haplogroups and PC. The mitochondrial DNA hypervariable segment I (HSV-1) was sequenced in a population-based study covering 168 cases (CA) and 140 unrelated healthy individuals as a control group (CG). A total of 92 different mtDNA sequences were found in CA and 59 were found in the CG. According to the geographical origin attributed to each mtDNA haplogroup, 82% of the mtDNA sequences found in both groups were Native Americans (A, B, C, and D). The most frequent was A (41.1%CA–42.1%CG), followed by B (22.0%CA–21.4%CG), C (12.0%CA–11.4%CG), and D (6%CA–10.0%CG). A lower percentage of European haplogroups (U, H, K, J, M, T, and HV) were also found (13.1%CA–12.9%CG), likewise African haplogroups (L0, L1, L2, and L3) (6.5%CA–2.1%CG). There were no statistically significant differences between the distribution of mtDNA haplogroups in CA and the CG in this study. 1. Introduction The precise molecular events leading to prostate carcinogenesis are currently not well known. The genetic characterization of this neoplasm has mainly been focused on the nuclear genome, showing complex chromosomal instability as one of the main changes; however, the cause of the diversity of chromosomal alterations detected in patients is still unclear. The presence of mutations in oncogenes and tumor suppressor genes has been associated with late events in the progression of prostate cancer (PC) [1]. Mitochondrial DNA (mtDNA) is the main target for cellular reactive oxygen species (ROS) and it has been observed that the level of oxidative damage is more extensive and persistent in this than in the nuclear genome, thereby leading to the accumulation of greater numbers of mutations [2]. Recent studies have shown that the presence of multiple homoplasmic point mutations in the mitochondrial genome is common in many human tumors, such as those found in colon and prostate cancers [3, 4]. These mutations could also lead to mitochondrial dysfunction due to alteration of the intermediary metabolism, which could be interpreted as a signal for inducing tumor pathogenesis [5]. The location of these mutations within the genome has been correlated with different types of cancer. The presence of
Association of Mitochondrial DNA Haplogroups with Exceptional Longevity in a Chinese Population  [PDF]
Xiao-yun Cai, Xiao-feng Wang, Shi-lin Li, Ji Qian, De-gui Qian, Fei Chen, Ya-jun Yang, Zi-yu Yuan, Jun Xu, Yidong Bai, Shun-zhang Yu, Li Jin
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006423
Abstract: Background Longevity is a multifactorial trait with a genetic contribution, and mitochondrial DNA (mtDNA) polymorphisms were found to be involved in the phenomenon of longevity. Methodology/Principal Findings To explore the effects of mtDNA haplogroups on the prevalence of extreme longevity (EL), a population based case-control study was conducted in Rugao – a prefecture city in Jiangsu, China. Case subjects include 463 individuals aged ≥95 yr (EL group). Control subjects include 926 individuals aged 60–69 years (elderly group) and 463 individuals aged 40–49 years (middle-aged group) randomly recruited from Rugao. We observed significant reduction of M9 haplogroups in longevity subjects (0.2%) when compared with both elderly subjects (2.2%) and middle-aged subjects (1.7%). Linear-by-linear association test revealed a significant decreasing trend of N9 frequency from middle-aged subjects (8.6%), elderly subjects (7.2%) and longevity subjects (4.8%) (p = 0.018). In subsequent analysis stratified by gender, linear-by-linear association test revealed a significant increasing trend of D4 frequency from middle-aged subjects (15.8%), elderly subjects (16.4%) and longevity subjects (21.7%) in females (p = 0.025). Conversely, a significant decreasing trend of B4a frequency was observed from middle-aged subjects (4.2%), elderly subjects (3.8%) and longevity subjects (1.7%) in females (p = 0.045). Conclusions Our observations support the association of mitochondrial DNA haplogroups with exceptional longevity in a Chinese population.
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